tbuckley/cabot-search huggingface dataset:
Abstract LB522: Fibroblast activation protein triggers the release of drug payload from non-internalizing small molecule-drug conjugates in solid tumors
Authors: Aureliano Zana, Andrea Galbiati, Ettore Gilardoni, Jacopo Millul, Theo Sturm, Riccardo Stucchi, Matilde Bocci, Abdullah Elsayed, Lisa Nadal, Martina Cirillo, Dario Neri, Samuele Cazzamalli
Journal: Cancer Research (2022)

Abstract Small Molecule-Drug Conjugates (SMDCs) are modular anti-cancer pro-drugs that include a tumor-targeting small ligand, a cleavable linker and a potent cytotoxic agent. SMDC products that have been developed for clinical applications are targeting internalizing tumor-associated antigens expressed on the surface of tumor cells. We have recently developed a novel non-internalizing small organic ligand (named OncoFAP) of Fibroblast Activation Protein (FAP), a tumor-associated antigen highly expressed in the stroma of most of solid human malignancies. The tumor targeting performance of OncoFAP has been validated by nuclear medicine studies in patients with various solid tumors. In a previous study, we showed that OncoFAP can be used to produce non-internalizing SMDCs that are effective and well tolerated. Here, we describe a new series of OncoFAP-Drug derivatives based on the MMAE tubulin poison and dipeptide linkers that are selectively cleaved by FAP in the tumor microenvironment. We benchmarked the new SMDCs against OncoFAP-MMAE conjugates displaying linker modules which are widely used in approved and clinical stage Antibody-Drug Conjugates, including structures cleaved by Cathepsin B and by reducing agents. We selected OncoFAP-GlyPro-MMAE as the most efficacious and safe SMDC for further clinical development after quantitatively analyzing the biodistribution of MMAE released by OncoFAP-MMAE conjugates. OncoFAP-GlyPro-MMAE selectively delivers high amounts of MMAE at the site of disease, with a tumor-to-kidney ratio of 7-to-1 and of 16-to-1 at 6- and 24-hours post-injection, respectively. Our molecules based on the OncoFAP tumor-targeting ligand and FAP-cleavable linkers promise to be safe and effective against most of human malignancies. Citation Format: Aureliano Zana, Andrea Galbiati, Ettore Gilardoni, Jacopo Millul, Theo Sturm, Riccardo Stucchi, Matilde Bocci, Abdullah Elsayed, Lisa Nadal, Martina Cirillo, Dario Neri, Samuele Cazzamalli. Fibroblast activation protein triggers the release of drug payload from non-internalizing small molecule-drug conjugates in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB522.
Abstract 3525: <i>Lactobacillus plantarum</i> IMB19 enhances anti-tumor immune response by modulating multi-layered innate and adaptive immunity
Authors: Garima Sharma, Amit Sharma, Inhae Kim, SooWoong Lee, Hae-Na Lee, ChangWook Park, Sin-Hyeog Im
Journal: Cancer Research (2022)

Abstract Intestinal commensals are being increasingly appreciated for their role in modulating the therapeutic efficacy of cancer therapies. Human-associated bacterial strains with demonstrable modulation of anti-tumor immune responses have great potential to be developed as biotherapeutics.We developed the AVATIOME࣪ model, a screening prototype based on murine primary immune cells, rationally targeting the innate and adaptive immune system to identify immuno-stimulating commensals.Our lead Lactobacillus plantarum IMB19 (Lp IMB19), suppresses tumor progression in pre-clinical models of melanoma, renal cancer, and NSCLC. LpIMB19 efficiently potentiates the therapeutic effect of anti-PD-L1 in murine tumor models. A capsular component of LpIMB19, structurally defined as rhamnose-rich hetero-polysaccharide (RHP) recapitulates the anti-tumor efficacy of live bacteria.The TLR2 agonist specifically targets macrophages towards an inflammatory phenotype followed by an increase in the activity of CD8+ IFNy+ T-cells. LpIMB19 and RHP enhance iron sequestration by activated macrophages in the tumor microenvironment through a defined mechanism. Thus, depriving tumor cells of iron and suppressing tumor cell proliferation. Translational investigations revealed the efficacy of LpIMB19 in urinary bladder xenograft studies.LpIMB19 mediated iron sequestration by inflammatory tumor macrophages, a byproduct of innate immune activation along with systemic CD8+ T-cells activation leads to enhancement of anti-tumor immunity. Our data on human cancers suggests the applicability of LpIMB19 as a potential onco-microbiotic. Currently, LpIMB19 is being progressed for clinical investigation as a live bio-therapeutic product (LBP) in combination with immune check-point inhibitors. Citation Format: Garima Sharma, Amit Sharma, Inhae Kim, SooWoong Lee, Hae-Na Lee, ChangWook Park, Sin-Hyeog Im. Lactobacillus plantarum IMB19 enhances anti-tumor immune response by modulating multi-layered innate and adaptive immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3525.
Abstract 1574: LSD-germline variant drive oncogenicity
Authors: Hyundong Yoon, Seulki Song, Yeeun Ha, Youngil Koh, SungSoo Yoon
Journal: Cancer Research (2022)

Abstract Lysosome storage disease (LSD) is a congenital metabolic disorder caused by mutations in genes involved in the function of lysosomes. Defects in the genes encoding hydrolases and transporters and enzyme activators are found in LSD’s, leading to the accumulation of macromolecules in the late endocytic system. And this disruption of lysosomal homeostasis increases the induction of endoplasmic reticulum and oxidative stress, proliferative signal transduction, extracellular matrix degradation, Integrin-β4-mediated cell migration and invasion, and consequently can promote the development of oncogenic cells and malignant tumors. It is known that the function of lysosomes is very important in cancer diseases. Recently, through a preliminary study, we found that the incidence of myeloproliferative neoplasm (MPN) increases statistically significantly when the LSD putative pathogenic germline variant (PPGV) is present. Based on this, we performed single-cell RNA (scRNA) sequencing using MPN patient samples of both LSD PPGV carrier and non-carrier. We tried to determine how the LSD PPGV affects MPN cancer progression at the single-cell level. To confirm functional differences between the two groups, DEG, pathway enrichment, LR-pair interaction, and transcription enrichment analyses were performed. In the analysis, immune cells were composed of T-cell, NK-cell, and Monocyte (in the order of frequency). It was confirmed that Lysosome-related (ER, Golgi, etc.) functions were upregulated in the carrier group compared to the non-carrier group across cell types. In addition, in the ligand-receptor (LR)-pair interaction analysis targeting Immune cells, it was possible to find a statistically significant difference (average log2 fold change&amp;gt;0.7 and p-value&amp;lt;0.05) candidate LR-pair (IL6-IL6R*IL6ST) that upregulates in the carrier group compared to the non-carrier group. The candidate LR-pair found by our team has been previously known as a cytokine-related gene that plays an inflammatory or fibrosis-related role in MPN and affects cancer progression. Also, in the Transcription Factor Enrichment analysis conducted together, it was confirmed that the statistically significant (NES&amp;gt;2 and FDR&amp;lt;0.01) candidate Transcription Factor (STAT1), which operates dependent on the candidate LR-pair, is upregulated. In conclusion, we found the possibility that genes and functions related to cancer progression can be up-regulated by LSD germline variants. In addition, we plan to conduct additional studies to determine the exact mechanism of contribution to cancer development by the LSD germline variant. Citation Format: Hyundong Yoon, Seulki Song, Yeeun Ha, Youngil Koh, SungSoo Yoon. LSD-germline variant drive oncogenicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1574.
Abstract 1809: Engineered destabilized ARE on the 3UTR of MYC degrades oncogenic c-MYC transcript and protein and induces apoptosis in multiple cancer types
Authors: Chidiebere Awah, Fu Dong, Yana Glemaud, Fayola Levine, Daniel Weiser, Olorunseun Ogunwobi
Journal: Cancer Research (2022)

Abstract The c-MYC oncogene is overexpressed in more than 18 human cancers, including triple negative breast cancer (TNBC), prostate cancer, and osteosarcoma, yet there is no clinically approved drug that targets this major oncogenic driver. We discovered that the 3’UTR of c-MYC in many cancers is enriched with stabilizing poly U tract sequences that can be destabilized with our novel engineered stabilizing AU Rich Elements (ARE), leading to degradation of c-MYC. We hypothesize that c-MYC destabilizing constructs will degrade c-MYC transcript and proteins across a range of cancers that overexpress this oncogene. We used heterogeneous panels of TNBC, prostate cancer, and osteosarcoma cell lines that are reflective of the heterogeneity of human cancers. We introduced our c-MYC destabilizing construct and assessed cell viability. We then performed immunofluorescence and western blot for assessment of c-MYC protein expression. Vector constructs were used as controls. Introduction of destabilizing elements achieved the degradation of both c-MYC transcript and proteins within four days, as well as a subsequent loss in cell viability. We observed that treated cells disintegrated from their nucleus, leading to increased active caspase 3/7 and cell death. Taken together, we have developed a novel technology that reliably targets and degrades the c-MYC oncogene across a range of highly aggressive and difficult to treat cancers Citation Format: Chidiebere Awah, Fu Dong, Yana Glemaud, Fayola Levine, Daniel Weiser, Olorunseun Ogunwobi. Engineered destabilized ARE on the 3UTR of MYC degrades oncogenic c-MYC transcript and protein and induces apoptosis in multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1809.
Use of <i>International Classification of Diseases, Tenth Revision, Clinical Modification</i> Z Codes to Identify Social Determinants of Health Among Surgical Patients
Authors: Gwyneth A. Sullivan, Yumiko Gely, Andrew Donaldson, Melissa Rangel, Brian C. Gulack, Ami N. Shah
Journal: JAMA Surgery (2022)

This cross-sectional study characterizes the use of International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) Z codes for social determinants of health among surgical vs nonsurgical practitioners at 3 academic hospitals.
Use of the new guidelines on an earlier age threshold of 35 years for diabetes screening can identify an additional 6.3 million undiagnosed individuals with diabetes and 72.3 million individuals with prediabetes among Chinese adults: An analysis of a nationally representative survey
Authors: Qiuyu Cao, Ruizhi Zheng, Ruixin He, Tiange Wang, Min Xu, Jieli Lu, Meng Dai, Di Zhang, Yuhong Chen, Zhiyun Zhao, Shuangyuan Wang, Hong Lin, Weiqing Wang, Guang Ning, Yufang Bi, Yu Xu, Mian Li
Journal: Metabolism (2022)
Abstract 5969: Intra-tumoral coagulation is significantly associated with EMT, angiogenesis, and worse patient survival in gastric cancer
Authors: Masanori Oshi, Joy Sarkar, Rongrong Wu, Li Yan, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe
Journal: Cancer Research (2022)

Abstract Background: Bleeding is one of the most commonly observed clinical signs of gastrointestinal cancer. Coagulation regulates inflammation and angiogenesis in cancer, and is associated with tumor development and metastasis. To date, there has been no measures to quantify the state of intra-tumoral coagulation. We hypothesized that intra-tumoral coagulation as quantified using coagulation score is associated with angiogenesis and worse prognosis in gastric cancer. Methods: The coagulation score was determined by the Gene set variation analysis (GSVA) algorithm as GSVA score of the “HALLMARK_COAGULATION” in the MSigDB hallmark gene sets collection. Transcriptome data of 807 gastric cancer patients of TCGA_STAD and GSE84437 cohorts were used for the analysis. Results: We found that high coagulation score was significantly associated with high AJCC T-category (p = 0.018), lymph node metastasis status (p = 0.036), AJCC stage (p = 0.006) in the TCGA cohort. The association of the score with staging were validated by GSE84437 cohort. Further, patients with high score were associated with worse disease-specific survival and overall survival (OS) (p = 0.019 and 0.011, respectively) in the TCGA cohort, and OS in GSE84437 cohort (p = 0.012). Although the coagulation score was not associated with cell proliferation-related nor immune-related signaling, gastric cancer with high coagulation score highly enriched epithelial mesenchymal transition (EMT), myogenesis, apical junction, transforming growth factor (TGF)-β signaling, and angiogenesis consistently in both cohorts (all false discovery rate&amp;lt;0.25). The coagulation score strongly correlated with angiogenesis score, and high coagulation was significantly associated with high infiltration of angiogenesis-related vascular cells, including endothelial cells, microvascular endothelial cells, lymphatic endothelial cells, and pericytes, calculated by xCell algorithm, as well as high expression of angiogenesis-related genes, including Endothelial cell marker, and vascular stability related genes. Conclusion: Intra-tumoral coagulation assessed by coagulation score is associated with clinical outcomes of gastric cancer patients. Citation Format: Masanori Oshi, Joy Sarkar, Rongrong Wu, Li Yan, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe. Intra-tumoral coagulation is significantly associated with EMT, angiogenesis, and worse patient survival in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5969.
Abstract 2931: Optical genome mapping workflow for identification and annotation of variants in hematological diseases
Authors: Jennifer Hauenstein, Andy Pang, Alka Chaubey, Alex Hastie
Journal: Cancer Research (2022)

Abstract Guidelines from WHO, NCCN and others, for the genetic analysis of hematological malignancies included structural variation analysis. Traditionally, this has relied on a combination of three cytogenetic technologies for structural variation analysis: karyotyping, FISH, and microarray, are used to detect copy number variants, translocations, inversions. Next generation sequencing is also applied for mutation analysis but has not been successful for structural variation analysis. These traditional methods have many very manual aspects and require extensive expertise. Optical genome mapping (OGM) consolidates assays into a single laboratory assay in which the output provides the visualization of structural and copy number variants at one time. OGM is able to comprehensively detect structural variations genome wide down to 5% variant allele fraction for CNVs, inversions, and translocations from blood and bone marrow aspirates making it an attractive choice for hematologic malignancy genomic analysis. Preanalytical and analytical steps require approximately 4-5 days from sample to processed data with structural variation calls. Dynamic filtering in the user interface can be configured to remove most polymorphic variants and prioritize relevant variants. In addition, the OGM graphical user interface software, Bionano Access 1.7, allows for the user to assign classification/relevance to the variants for each case. For example, an ALL sample with t(9;22), deletion of CDKN2A, and whole chromosome gains of 4,6, and 10 can be easily visualized with the Circos plot and, then, can be further examined and annotated as needed. A second analyst can repeat the process blind to the first analysis and a supervisor can adjudicate the classifications. A variety of cases with hallmark abnormalities from various leukemias will be presented with the filtering and prioritization workflow used to derive them. This comprehensive technology allows for a quicker, more reliable output than traditional cytogenetic approaches. Citation Format: Jennifer Hauenstein, Andy Pang, Alka Chaubey, Alex Hastie. Optical genome mapping workflow for identification and annotation of variants in hematological diseases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2931.
Increase in serum choline levels predicts for improved progression-free survival (PFS) in patients with advanced cancers receiving pembrolizumab
Authors: Geoffrey Alan Watson, Enrique Sanz-Garcia, Wen-Jiang Zhang, Zhihui Amy Liu, SY Cindy Yang, Ben Wang, Shaofeng Liu, Shawn Kubli, Hal Berman, Thomas Pfister, Sofia Genta, Anna Spreafico, Aaron R Hansen, Philippe L Bedard, Stephanie Lheureux, Albiruni Abdul Razak, Dave Cescon, Marcus O Butler, Wei Xu, Tak W Mak, Lillian L Siu, Eric Chen
Journal: Journal for ImmunoTherapy of Cancer (2022)

Recent studies have demonstrated that T cells can induce vasodilation in a choline-acetyltransferase dependent manner, leading to an increase in T cell migration to infected tissues in response to viral infection, but its role in cancer is unclear. Choline acetyltransferase catalyzes the production of acetylcholine from choline and acetyl-CoA, however, acetylcholine is challenging to quantify due to its extremely short half-life while choline is stable. This study aims to correlate serum choline levels in patients with advanced solid tumors receiving pembrolizumab with treatment outcomes.Blood samples were collected at baseline and at week 7 (pre-cycle 3) in patients treated with pembrolizumab in the INvestigator-initiated Phase 2 Study of Pembrolizumab Immunological Response Evaluation phase II trial (NCT02644369). Samples were analyzed for choline and circulating tumor DNA (ctDNA). Multivariable Cox models were used to assess the association between choline and overall survival (OS) and progression-free survival (PFS) when including ΔctDNAC3 (the change in ctDNA from baseline to cycle 3), cohort, PD-L1 expression and tumor mutation burden (TMB). An independent validation cohort from the LIBERATE study (NCT03702309) included patients on early phase trials treated with a PD-1 inhibitor.A total of 106 pts were included in the analysis. With a median follow-up of 12.6 months, median PFS and OS were 1.9 and 13.7 months, respectively. An increase in serum choline level at week 7 compared with baseline (ΔcholineC3) in 81 pts was significantly associated with a better PFS (aHR 0.48, 95% CI 0.28 to 0.83, p=0.009), and a trend toward a better OS (aHR 0.64, 95% CI 0.37 to 1.12, p=0.119). A combination of ΔctDNAC3 and ΔcholineC3 was prognostic for both OS and PFS. Multivariable analyses show ΔcholineC3 was a prognostic factor for PFS independent of ΔctDNAC3, cohort, PD-L1 and TMB. In the independent validation cohort (n=51), an increase in serum choline at cycle 2 was associated with a trend to improved PFS.This is the first exploratory report of serum choline levels in pan-cancer patients receiving pembrolizumab. The association between improved PFS and ΔcholineC3 suggests a possible role for the cholinergic system in the regulation of antitumor immunity. Further pre-clinical and clinical studies are required to validate this finding.NCT03702309.
Abstract 5039: Visualization and analysis of cancer genomics data using UCSC Xena
Authors: Mary Goldman, Brian Craft, Jingchun Zhu, David Haussler
Journal: Cancer Research (2022)

Abstract UCSC Xena (http://xena.ucsc.edu/) is a web-based visual integration and exploration tool for multi-omic data and associated clinical and phenotypic annotations. Researchers can easily view and explore public data, their own private data, or both using the Xena Browser. Private data are kept on the researcher's computer and are never uploaded to our public servers. The toll supports Mac, Windows, and Linux. Questions Xena can help you answer: 1) Is overexpression of this gene associated with lower/higher survival? 2) What genes are differentially expressed between these two groups of samples? 3) What is the relationship between mutation, copy number, expression, etc for this gene? Xena showcases seminal cancer genomics datasets from TCGA, the Pan-Cancer Atlas, GDC, PCAWG, ICGC, and more; a total of more than 1500 datasets across 50 cancer types. We support virtually any type of functional genomics data: SNPs, INDELs, copy number variation, gene expression, ATAC-seq, DNA methylation, exon-, transcript-, miRNA-, lncRNA-expression, and structural variants. We also support clinical data such as phenotype information, subtype classifications and biomarkers. All of our data is available for download via python or R APIs, or using our URL links. Our signature Visual Spreadsheet view shows multiple data types side-by-side enabling discovery of correlations across and within genes and genomic regions. We also have dynamic Kaplan-Meier survival analysis, powerful filtering and subgrouping, differential gene expression analysis, charts, statistical analyses, genomic signatures, and the ability to generate URLs to live views. We link out to the UCSC Genome Browser as well as MuPIT/CRAVAT and TumorMap. New features include: - Genome-wide differential gene expression analysis - New interface for filtering samples and creating subgroups - New interface to create charts and graphs - Violin plots on any numerical data - Loading of Microsoft Excel files - A new Publication Page showcasing publications and authors that use UCSC Xena Our beta prototype for visualizing single-cell data delivers million-cell-scale multi-omics data for interactive visualization in a web browser. Citation Format: Mary Goldman, Brian Craft, Jingchun Zhu, David Haussler. Visualization and analysis of cancer genomics data using UCSC Xena [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5039.